Methods, agents and peptides for inhibiting matrix metalloproteinase-2 signaling
a matrix metalloproteinase and signaling technology, applied in the direction of antibody medical ingredients, instruments, drug compositions, etc., can solve the problems of limited therapeutic efficacy of these approaches, and achieve the effects of improving immune responses, improving th1 responses, and improving therapeutic efficacy
Inactive Publication Date: 2014-10-23
NEW YORK UNIV
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Benefits of technology
The patent text describes a method for identifying a modulator of matrix metalloproteinase-2 (MMP-2) that can activate TLR-2, a receptor that plays a role in the immune response to melanoma and other tumors that express MMP-2. The method involves contacting a composition of TLR-2 and MMP-2 with a candidate modulator agent and measuring the change in TLR-2 / MMP-2 interaction levels in the presence of the modulator agent. The change in interaction levels indicates the effectiveness of the modulator agent in inducing an immune response. The invention provides a method for improving immune responses to melanoma and other tumors that express MMP-2 by targeting TLR-2. The patent also describes a MMP-2 peptide that can be used as a vaccine to treat melanoma and other tumors that express MMP-2.
Problems solved by technology
The therapeutic efficacy of these approaches remains limited, however, indicating an urgent need for improved strategies.
Method used
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Introduction
[0169]Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme that degrades the extracellular matrix and is over-expressed by many tumors. The present inventors have previously documented the presence of MMP-2-specific CD4+ T cells in tumor-infiltrating lymphocytes (TILs) from melanoma patients, which display an inflammatory TH2 profile, i.e. mainly secreting TNFα, IL-4 and IL-13 and expressing GATA-3. The present inventors, furthermore, demonstrated that MMP-2-conditioned dendritic cells (DCs) prime naive CD4+ T cells to differentiate into an inflammatory TH2 phenotype through OX40L expression and inhibition of IL-12p70 production. Active MMP-2, therefore, acts as a novel endogenous type-2 “conditioner” and may play a role in the observed prevalence of detrimental type-2 responses in melanoma.
[0170]As shown herein, the present inventors demonstrate that MMP-2 directed conditioning toward detrimental type-2 responses in MMP-2 expressing tumors (e.g., melanoma) is driv...
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Abstract
Screening assays and methods of using same for screening to identify modulator agents or compounds that affect matrix metalloproteinase-2 (MMP-2) mediated activation of toll-like receptor-2 (TLR-2) are described herein. Pharmaceutical and immunogenic compositions comprising agents or compounds that modulate MMP-2 mediated activation of TLR-2 are also encompassed. Methods for modulating MMP-2 mediated activation of TLR-2 using MMP-2 peptides in pharmaceutical and immunogenic compositions, as well as vaccines, are also envisioned. Melanoma is an exemplary tumor type that expresses MMP-2 and for which such pharmaceutical and immunogenic compositions, as well as vaccines, would confer benefit to patients. Also encompassed are methods for reducing MMP-2 mediated activation of TLR-2 and downstream signaling therefrom so as to achieve more effective T cell responses to MMP-2 expressing tumors.
Description
GOVERNMENTAL SUPPORT[0001]The research leading to the present invention was supported, at least in part, by National Institutes of Health Grant Nos. R01 AI071078 and 1R01AI061684. Accordingly, the Government has certain rights in the invention.FIELD OF THE INVENTION[0002]The present invention relates to methods for screening to identify modulator agents or compounds that affect matrix metalloproteinase-2 (MMP-2) mediated activation of toll-like receptor-2 (TLR-2). Also encompassed herein are methods for modulating MMP-2 mediated activation of TLR-2 and to the application of MMP-2 peptides for pharmaceutical and immunogenic compositions, as well as vaccines. Pharmaceutical and immunogenic compositions comprising agents or compounds that modulate MMP-2 mediated activation of TLR-2 are also encompassed herein. Melanoma is an exemplary tumor type that expresses MMP-2 and for which such pharmaceutical and immunogenic compositions, as well as vaccines, would confer benefit to patients. Th...
Claims
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IPC IPC(8): A61K39/00G01N33/573C12Q1/37
CPCA61K39/0011G01N33/573C12Q1/37C07K16/2896C07K2317/76G01N33/566G01N2333/52G01N2333/96494A61K39/00C12N9/6491A61P29/00A61K39/001159A61K39/4611A61K39/464459A61K39/464457
Inventor GODEFROY, EMMANUELLEBHARDWAJ, NINA
Owner NEW YORK UNIV